CN116462627A - Preparation method of 3-bromopiperidine-2, 6-dione - Google Patents
Preparation method of 3-bromopiperidine-2, 6-dione Download PDFInfo
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- CN116462627A CN116462627A CN202310421972.7A CN202310421972A CN116462627A CN 116462627 A CN116462627 A CN 116462627A CN 202310421972 A CN202310421972 A CN 202310421972A CN 116462627 A CN116462627 A CN 116462627A
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- Prior art keywords
- reaction
- bromopiperidine
- dione
- filter cake
- preparing
- Prior art date
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- RYSICGXZRVMXDP-UHFFFAOYSA-N 3-bromopiperidine-2,6-dione Chemical compound BrC1CCC(=O)NC1=O RYSICGXZRVMXDP-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000007858 starting material Substances 0.000 claims abstract description 9
- 238000007112 amidation reaction Methods 0.000 claims abstract description 5
- 238000005893 bromination reaction Methods 0.000 claims abstract description 5
- LIBFVQBAZPYQCJ-UHFFFAOYSA-N 2-oxaspiro[3.4]octane-1,3-dione Chemical compound O=C1OC(=O)C11CCCC1 LIBFVQBAZPYQCJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 21
- 239000012065 filter cake Substances 0.000 claims description 20
- 239000000047 product Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000010992 reflux Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- ZKWDCFPLNQTHSH-UHFFFAOYSA-N tribromoisocyanuric acid Chemical compound BrN1C(=O)N(Br)C(=O)N(Br)C1=O ZKWDCFPLNQTHSH-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 238000005422 blasting Methods 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 9
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 238000001514 detection method Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention belongs to the technical field of medical intermediates, and particularly relates to a preparation method of 3-bromopiperidine-2, 6-dione, wherein the 3-bromopiperidine-2, 6-dione is prepared by taking cyclopentanedioic anhydride as a starting material, and performing amidation reaction and TBICA bromination reaction to obtain a finished product. The preparation method of the 3-bromopiperidine-2, 6-dione provided by the invention is a brand new preparation method and has the advantages of safety, environmental protection and easiness in large-scale production.
Description
Technical Field
The invention belongs to the technical field of medical intermediates, and particularly relates to a preparation method of 3-bromopiperidine-2, 6-dione.
Background
3-bromopiperidine-2, 6-dione is an important pharmaceutical intermediate, CAS number 62595-74-8, molecular formula C 5 H 6 BrNO 2 。
The preparation principle of the existing 3-bromopiperidine-2, 6-dione is shown as follows after searching:
Ref:1)WO200992764.2)WO2017161119.3)WO2019140387.4)WO201333901.
the method comprises the following steps: the use of relatively expensive cyclopentadiimides as starting materials; bromine is adopted as a brominating reagent, and the bromine has high toxicity and irritation and complex post-treatment; chloroform was used as a solvent; the reaction needs high temperature (110 ℃) and tube sealing reaction, has high risk, and is not easy to prepare in large batch; the yield is generally not ideal (about 30 to 50%).
Therefore, it is necessary to provide a novel, safe, environment-friendly and easy-to-scale-up preparation method of 3-bromopiperidine-2, 6-dione.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provide a preparation method of 3-bromopiperidine-2, 6-dione.
In order to achieve the technical purpose and the technical effect, the invention is realized by the following technical scheme:
the preparation method of 3-bromo-piperidine-2, 6-dione is characterized in that the 3-bromo-piperidine-2, 6-dione is prepared by taking cyclopentanedioanhydride as a starting material, and performing amidation reaction and TBICA bromination reaction to obtain a finished product.
Further, the reaction in the first step is shown as a formula (I), and an intermediate A is obtained after the reaction:
further, the reaction in the first step comprises the following specific steps: sequentially adding isopropanol, 25% ammonia water and cyclopentanedioanhydride into a reaction kettle, stirring and dissolving, heating to 85 ℃ and carrying out reflux reaction for 2-6h; TLC monitors that the raw materials are completely reacted, slowly cooling to room temperature, crystallizing, filtering, washing a filter cake by using a mixed solution prepared by mixing isopropyl alcohol and water, and drying the filter cake by blasting to obtain an intermediate A.
Further, the filter cake is washed in three batches by using a mixed solution prepared by mixing isopropanol and water according to a volume ratio of 1:1.
Further, the filter cake was air dried at 100℃for 6-18h to give intermediate A.
Further, the reaction in the second step is shown as a formula (II), and a finished product is obtained after the reaction:
further, the reaction of the second step comprises the following specific steps: adding ethanol into a reaction kettle, adding the intermediate A into the reaction kettle, stirring at room temperature for dissolution, adding tribromoisocyanuric acid into the reaction system in batches, heating to 85 ℃, stirring and refluxing for reaction for 1-3h; TLC monitors that the raw materials are completely reacted, cooling to room temperature, filtering to remove insoluble substances, washing a filter cake with ethanol in three batches, combining filtrates, transferring to a reaction kettle, adding water, and heating and refluxing until the solid is completely dissolved; slowly cooling, crystallizing, filtering, washing filter cake with mixed solution prepared by mixing ethanol and water, and vacuum drying filter cake to obtain the final product.
Further, the filter cake is washed twice by a mixed solution prepared by mixing ethanol and water according to the volume ratio of 2:1.
Further, the filter cake is dried in vacuum at 60 ℃ for 12-48 hours to obtain the finished product.
The beneficial effects of the invention are as follows:
the 3-bromopiperidine-2, 6-dione is prepared by taking cyclopentanedioic anhydride as a starting material, and performing amidation reaction and TBICA bromination reaction to obtain a finished product in two steps; the preparation method is a brand new preparation method and has the advantages of safety, environmental protection and easy scale-up production.
Of course, it is not necessary for any one product to practice the invention to achieve all of the advantages set forth above at the same time.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed for the description of the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a diagram showing the NMR detection result of the product of the present invention;
FIG. 2 is a second diagram of the NMR detection result of the product of the invention;
FIG. 3 is a schematic diagram of LCMS detection results of the finished product of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The concrete terms of the embodiment are as follows:
SM: cyclopentanedioic anhydride
IPA: isopropyl alcohol
TBICA: tribromoisocyanuric acid
EtOH: ethanol
The specific embodiment of the invention is as follows:
example 1
The preparation method of 3-bromo-piperidine-2, 6-dione is characterized in that the 3-bromo-piperidine-2, 6-dione is prepared by taking cyclopentanedioanhydride as a starting material, and performing amidation reaction and TBICA bromination reaction to obtain a finished product.
The reaction in the first step is shown in a formula (I), and an intermediate A is obtained after the reaction:
the reaction in the first step comprises the following specific steps: isopropanol (6L), 25% ammonia (6L, 10.0 eq) and SM (1000.0 g,1.0 eq) were added into a reaction kettle in sequence, stirred and dissolved, and heated to 85 ℃ for reflux reaction for 4h. TLC monitored complete reaction of the starting material, slow down to room temperature, crystallization, filtration, cake with isopropanol: water = 1:1 (v/v) solution (1L) was washed in three batches and the filter cake was air dried at 100 ℃ for 12h to give intermediate a as a white solid powder 933.9g in 94.2% yield.
Mass spectrometry: MS-ESI:114.1[ M+H ]] + 。
The reaction in the second step is shown in the formula (II), and a finished product is obtained after the reaction:
the second step of reaction comprises the following specific steps: etOH (5L) was added to the reaction vessel, intermediate A (933.9 g,1.0 eq.) was added to the reaction vessel, dissolved by stirring at room temperature, TBICA (1026.7 g,0.34 eq.) was added to the reaction system in portions, and the mixture was heated to 85℃and reacted under reflux with stirring for 2 hours. TLC monitors complete reaction of the raw materials, cools to room temperature, filters to remove insoluble substances, washes a filter cake with ethanol (3L) in three batches, combines filtrates, transfers to a reaction kettle, adds water (4L), heats and refluxes until the solid is completely dissolved, slowly cools and cools for crystallization, filters, and uses ethanol for filter cake: water=2:1 (v/v) mixture (2L) was washed twice and the filter cake was dried under vacuum at 60 ℃ for 24h to give 1456.8g of TM pure product with a yield of 91.9%.
Mass spectrometry: MS-ESI:194.1/192.1[ M+H ]] +
The results of the product related tests are shown in fig. 1 to 3.
The preferred embodiments of the invention disclosed above are intended only to assist in the explanation of the invention. The preferred embodiments are not exhaustive or to limit the invention to the precise form disclosed. Obviously, many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and the practical application, to thereby enable others skilled in the art to best understand and utilize the invention. The invention is limited only by the claims and the full scope and equivalents thereof.
Claims (9)
1. A preparation method of 3-bromo-piperidine-2, 6-dione is characterized by comprising the following steps: the 3-bromopiperidine-2, 6-dione is prepared by taking cyclopentanedioic anhydride as a starting material, and performing amidation reaction and TBICA bromination reaction to obtain a finished product in two steps.
2. The process for preparing 3-bromopiperidine-2, 6-dione according to claim 1, wherein the reaction in the first step is represented by formula (I), and intermediate a is obtained after the reaction:
3. the method for preparing 3-bromopiperidine-2, 6-dione according to claim 2, wherein the reaction of the first step comprises the following specific steps: sequentially adding isopropanol, 25% ammonia water and cyclopentanedioanhydride into a reaction kettle, stirring and dissolving, heating to 85 ℃ and carrying out reflux reaction for 2-6h; TLC monitors that the raw materials are completely reacted, slowly cooling to room temperature, crystallizing, filtering, washing a filter cake by using a mixed solution prepared by mixing isopropyl alcohol and water, and drying the filter cake by blasting to obtain an intermediate A.
4. A process for the preparation of 3-bromopiperidine-2, 6-dione as claimed in claim 3, wherein the filter cake is washed in three batches with a mixture of isopropanol and water in a volume ratio of 1:1.
5. A process for the preparation of 3-bromopiperidine-2, 6-dione according to claim 3, characterized in that the filter cake is air dried at 100 ℃ for 6-18h to give intermediate a.
6. The process for preparing 3-bromopiperidine-2, 6-dione according to claim 3, wherein the reaction in the second step is represented by formula (II):
7. the method for preparing 3-bromopiperidine-2, 6-dione according to claim 6, wherein the reaction in the second step comprises the following specific steps: adding ethanol into a reaction kettle, adding the intermediate A into the reaction kettle, stirring at room temperature for dissolution, adding tribromoisocyanuric acid into the reaction system in batches, heating to 85 ℃, stirring and refluxing for reaction for 1-3h; TLC monitors that the raw materials are completely reacted, cooling to room temperature, filtering to remove insoluble substances, washing a filter cake with ethanol in three batches, combining filtrates, transferring to a reaction kettle, adding water, and heating and refluxing until the solid is completely dissolved; slowly cooling, crystallizing, filtering, washing filter cake with mixed solution prepared by mixing ethanol and water, and vacuum drying filter cake to obtain the final product.
8. The method for preparing 3-bromopiperidine-2, 6-dione according to claim 7, wherein the cake is washed twice with a mixed solution prepared by mixing ethanol and water in a volume ratio of 2:1.
9. The method for preparing 3-bromopiperidine-2, 6-dione according to claim 7, wherein the cake is dried under vacuum at 60 ℃ for 12-48 hours to obtain a finished product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310421972.7A CN116462627A (en) | 2023-04-19 | 2023-04-19 | Preparation method of 3-bromopiperidine-2, 6-dione |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310421972.7A CN116462627A (en) | 2023-04-19 | 2023-04-19 | Preparation method of 3-bromopiperidine-2, 6-dione |
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| Publication Number | Publication Date |
|---|---|
| CN116462627A true CN116462627A (en) | 2023-07-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310421972.7A Pending CN116462627A (en) | 2023-04-19 | 2023-04-19 | Preparation method of 3-bromopiperidine-2, 6-dione |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116462627A (en) |
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2023
- 2023-04-19 CN CN202310421972.7A patent/CN116462627A/en active Pending
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